COGNITIVE BEHAVIORAL TREATMENT OF INSOMNIA SLOWS THE PACE OF BIOLOGICAL AGING: RESULTS FROM AN RCT IN OLDER ADULTS

Abstract Insomnia in late life has been linked to accelerated biological aging, presenting a behaviorally modifiable target to slow the pace of aging. We previously demonstrated that treatment of insomnia in older adults using cognitive behavioral therapy for insomnia (CBT-I) reduced the expression of the cellular senescence marker, p16INK4a, in peripheral blood mononuclear cells (PBMC). Next, we tested whether this treatment for insomnia would alter the biological pace of aging, estimated from the DNA methylation derived DunedinPACE, as compared to a sleep education therapy (SET), an active comparator condition. Participants 60+ years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I (n=49) or SET (n=45). Epigenetic data were obtained from DNA extracted from blood collected prior to initiation of treatment (baseline) and again 18-24 months later. A mixed linear models adjusting for age, sex, BMI, and education revealed a significant treatment by time interaction (p=0.003). Receipt of CBT-I was associated with a decline in the epigenetic pace of aging, while those receiving SET had an increase in their pace of aging. Findings indicate that a behavioral intervention to improve insomnia was effective at slowing the pace of biological aging among older adults. Future research will be needed to replicate these findings in other age groups and specific populations with heightened risk for accelerated aging.

electronic health records from the Clinical Data Analysis and Reporting System in Hong Kong.People aged 40+ who had an incident depression diagnosis between 2001 and 2015 were included and followed up until 31 December 2018.Latent class analysis was applied, separately by decades, to individuals with depression and at least one comorbid somatic condition.Cox proportional hazard models were used to examine the risk of mortality associated with specific comorbidity patterns, adjusting for sociodemographic and clinical characteristics.We identified 38,889 eligible individuals (mean age: 62.8; 68.7% women).Latent class analysis identified an increasing number of patterns with age (two to seven).Compared with the unspecific pattern, the following patterns were associated with the highest mortality risk in different age groups: cardiometabolic and cerebrovascular diseases in individuals aged 40-49 (hazard ratio [HR] 2.5 [95% CI 1.7-3.7]),cardiometabolic diseases and anemia in those aged [50][51][52][53][54][55][56][57][58][59]) and 70-79 (2.7 [2.3-3.3]),cardiometabolic, cerebrovascular diseases, and anemia in those aged 60-69 (HR 2.5 [2.0-3.2]), and cardiorespiratory disease in those aged 80+ ).Specific somatic comorbidity patterns were independently and substantially associated with the risk of mortality.This highlights the importance of taking combinations of somatic conditions into account when tailoring the clinical and care approach to people with depression.

CASUAL EFFECTS OF EARLY-LIFE ADVERSITY AND MID/LATE-LIFE BEHAVIORAL INTERVENTION ON THE PACE OF BIOLOGICAL AGING
Chair: Daniel Belsky Discussant: Luigi Ferrucci Epigenetic clocks have taken gerontology by storm.With the advent of 2nd and 3rd generation epigenetic clocks, including GrimAge and DunedinPACE, the field now has genomic biomarkers of aging that exhibit strong and consistent associations with aging-related morbidity and mortality.But the causes of variation in these powerful indices of aging-related biological changes remain poorly understood.In this symposium, we present four studies at the vanguard of research to elucidate causal drivers of 2nd and 3rd generation epigenetic clocks drawn from four disciplines.From life-course epidemiology, we present a natural-experiment study of the long-term impact of in-utero famine exposure.From economics, we present a quasi-natural experiment study of long-term impacts of early-life exposure to the Great Depression.From psychology, we present results from a randomized controlled trial (RCT) of cognitive behavioral therapy (CBT) for insomnia in older adults.And from geroscience, we present results from an RCT of long-term calorie restriction in healthy, non-obese adults (CALERIE).These studies report novel and important findings that suggest early-life adversity acts to accelerate the pace of biological aging -and-that it may be possible to slow the pace of biological aging in mid-and later-life through behavioral intervention.They also illustrate study designs and methods that can help move the field forward as costs for measurement of epigenetic clocks fall, enabling their introduction into many more cohort and intervention studies.

EFFECT OF LONG-TERM CALORIC RESTRICTION ON THE PACE OF BIOLOGICAL AGING IN HEALTHY ADULTS FROM THE CALERIE TRIAL Daniel Belsky, Columbia University, New York City, New York, United States
The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan.Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, can change molecular processes associated with aging, including DNA methylation (DNAm), and increases healthy lifespan in multiple species.Here we report results of a post-hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n=220 non-obese adults were randomized to 25% CR or ad libitum control diet for 2 years.We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm clock, but did not lead to significant changes in PhenoAgeor GrimAge-clock-measured biological age.Treatment effects were small; changes in DunedinPACE suggest a ~3% slowing of the pace of aging.Nevertheless, this small effect may be substantive; in an independent study of older adults, 3% slower DunedinPACE is associated with a 15% lower risk of death.The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies and contrasting with reports that biological aging may not be modifiable.Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.

COGNITIVE BEHAVIORAL TREATMENT OF INSOMNIA SLOWS THE PACE OF BIOLOGICAL AGING: RESULTS FROM AN RCT IN OLDER ADULTS Judith Carroll, University of California, Los Angeles, Los Angeles, California, United States
Insomnia in late life has been linked to accelerated biological aging, presenting a behaviorally modifiable target to slow the pace of aging.We previously demonstrated that treatment of insomnia in older adults using cognitive behavioral therapy for insomnia (CBT-I) reduced the expression of the cellular senescence marker, p16INK4a, in peripheral blood mononuclear cells (PBMC).Next, we tested whether this treatment for insomnia would alter the biological pace of aging, estimated from the DNA methylation derived DunedinPACE, as compared to a sleep education therapy (SET), an active comparator condition.Participants 60+ years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I (n=49) or SET (n=45).Epigenetic data were obtained from DNA extracted from blood collected prior to initiation of treatment (baseline) and again 18-24 months later.A mixed linear models adjusting for age, sex, BMI, and education revealed a significant treatment by time interaction (p=0.003).Receipt of CBT-I was associated with a decline in the epigenetic pace of aging, while those re-survivors of in-utero famine exposure, matched controls born in the same hospitals as the survivors immediately prior to and following the famine period, and siblings of these individuals.Blood samples were collected when the famine survivors were aged 58.We analyzed blood DNA methylation data to measure the GrimAge and PhenoAge 2nd-generation epigenetic clocks and the DunedinPACE 3rd-generation clock.We tested if famine survivors were biologically older and aging faster as compared to controls.We found that famine survivors had faster DunedinPACE pace of aging, as compared with controls, but similar PhenoAge and GrimAge biological ages.In sex-stratified analyses, we found stronger effects of famine exposure in women as compared with men, including for the GrimAge and PhenoAge clocks; among women, famine exposure was associated with faster DunedinPACE and older GrimAge and PhenoAge, whereas in men effect-sizes were near zero.Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation.Siblingdifference analyses reproduced size and direction of effect estimates.Findings provide natural-experiment evidence for long-term effects of in-utero famine exposure on the pace biological aging.In this symposium we examine the extent to which psychosocial interventions might promote healthy aging among women with emotional, mobility, and sensory limitations.A growing literature explains the need for culturally tailored care for men and women with disabilities while also stressing the importance of accommodations when living in inaccessible environments.Creating positive social participation amongst diverse groups based on sex/gender with varying levels of function and types of limitations may require more thought and resources than society is willing to forfeit.In this symposium, we begin by examining these issues among people aging in Mexico with few environmental accommodations in place.Creating recognition for the needs of men compared to women who age into mobility limitations in Mexico begins with identifying their unique individual and environmental risks.Next, we examine the needs of women in acute and long-term care with schizophrenia related emotional limitations.Stigma and neglect may create an environmental barrier to healthy aging in the U.S among this population.Our next study examines how sleep duration and quality can impact levels of depression and fatigue for men and women with sensory limitations, drawing attention to the additive effects of emotional changes on functional limitations.Finally, Taylor's group draws our attention to the work of creating social participation interventions for depression among African American women as they age with severe arthritic pain.We conclude by facilitating a discussion on social and cultural barriers for diverse women aging with functional limitations.This is a Women's Issues Interest Group Sponsored Symposium.
IMPACT ON DISABILITY WITH AGE Chair: Tracie Harrison Co-Chair: Corey Nagel Discussant: Tracie Harrison